Tauopathies are a group of neurodegenerative diseases characterized by accumulation of tau (τ) protein in the brain. AD is the most prevalent of the tauopathies and the most common form of dementia. Other tauopathies and related neurodegenerative diseases include Pick's disease, progressive supranuclear palsy, corticobasal degeneration, hereditary fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).
Dementia is a brain disorder that seriously affects a person's ability to carry out normal daily activities. AD involves parts of the brain that control thought, memory, and language. Despite intensive research throughout the world, the causes of AD, except for rare reported cases of familial AD gene mutations, are still unknown and there is no cure.
There are several treatments for the cognitive symptoms of AD currently available. Of the five drugs currently being used in the United States for the treatment of AD, four of them are inhibitors of acetylcholinesterase. Another drug, memantine, an NMDA receptor antagonist, is available for treating moderate-to-severe AD. The drugs currently used for treating the cognitive symptoms of AD, including memantine and the acetylcholine esterase inhibitors, are marginally efficacious, and have not been shown to effectively slow or stop the progression of the disease. There is an increased interest in the development of therapies to impede the pathologic progression of AD because the pathophysiologic process leading to neurodegeneration in AD is thought to begin long before clinical symptoms develop. Thus, there is a large unmet need for drugs that may slow or stop the pathological progression of AD, and other tauopathies and neurodegenerative diseases.
The histamine H3 receptors are found in the central and peripheral nervous systems. The administration of histamine H3 receptor ligands may influence the secretion of neurotransmitters in the brain and the periphery and have been considered useful in the treatment of cognitive disorders, including AD and other dementias. Brioni et al. note that H3 antagonists could possibly be used for disease-modifying therapy in AD (The Journal of Pharmacology and Experimental Therapeutics, Vol. 336, No. 1, 38-46 (2011)).
The present invention is based on the novel result from preclinical studies that treatment with 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide can slow down the progression of tau pathology in a transgenic animal model at doses consistent with those used in the human population.